By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P < 5 × 10−8. These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.
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We acknowledge funding from: the Academy of Finland (no. 124243); Agence Nationale de la Recherche (France); American Diabetes Association (1-05-RA-140, 7-08-MN-OK; 7-06-MN-05); Ardix Medical; Association Diabète Risque Vasculaire; Association de Langue Française pour l'Etude du Diabète et des Maladies Métaboliques; Association Française des Diabétiques; Bayer Diagnostics; British Diabetic Association Research; Becton Dickinson; Broad Institute of Harvard and Massachusetts Institute of Technology; The Burroughs Wellcome Fund; Cardionics; Center for Inherited Disease Research (USA); Centre for Medical Systems Biology (The Netherlands); Centre of Excellence Metabolic Disorders Baden-Wuerttemberg (Germany); Caisse Nationale Assurance Maladie des Travailleurs Salariés (France); Clinical Research Institute HUCH Ltd; Deutsche Forschungsgemeinschaft (DFG GrK 1041, DFG RA459, SFB 518); the Danish Diabetes Association; the Danish Health Research Council; Diabetes UK; Doris Duke Charitable Foundation; Erasmus Medical Center (The Netherlands); the Dutch Diabetes Foundation; European Community (HEALTH-F4-2007-201413, HEALTH-2007-B-223211, LSHG-CT-2006-01947, LSHM-CT-2004-512013, LSHM-CT-2004-005272, LSHM-CT-2006-518153); the European Foundation for the Study of Diabetes; the Federal Ministry of Health (Germany); the Federal Ministry of Education and Research (Germany) (FKZ01GS0823 and DZD e.V.); Fédération Française de Cardiologie; The Finnish Diabetes Research Foundation; The Folkhalsan Research Foundation; The Foundation for Strategic Research (Sweden); The Foundation of Bristol-Myers Squibb; the German National Genome Research Network; Helmholtz Zentrum München-Research Center for Environment and Health; INSERM (France); La Fondation de France; Lilly; The Linnaeus Centre for Bioinformatics (Sweden); the Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction, Prevention and Care; the Medical Research Council UK (G0601261, G0000649; 081696); Munich Center of Health Sciences-LMU Innovativ (Germany); Merck Santé; the Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano (Italy); the Ministry of Innovation, Science, Research and Technology of the State of North Rhine-Westphalia (Germany); the Ministry of Science, Education and Sport (Croatia); the National Heart, Lung, and Blood Institute (N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N01-HC-25195, R01HL087641, R01HL59367, R01HL086694, N02-HL-6-4278); National Human Genome Research Institute (U01HG004402, U01HG004399, U01HG004171, 1 Z01 HG000024); the National Institute of Diabetes, Digestive and Kidney Diseases (DK078616, K24-DK080140, U54 DA021519, DK58845, DK069922, DK062370, DK073490, K23-DK65978 and DK072193); the US National Institutes of Health (HHSN268200625226C, HHSN268200625226C, 1K08AR055688, UL1RR025005, 1K99HL094535-01A1); the Netherlands Foundation for Scientific Research (175.010.2005.011, 047.017.043); Nord-Pas-de-Calais region (France); Novartis Pharma; Novo Nordisk; the Oxford National Institute for Health Research (NIHR) Biomedical Research Centre (UK); Office National Inter-professionnel des Vins; Peninsula Medical School, Exeter UK; Pfizer, Inc; Pierre Fabre laboratory (France); Programme National de Recherche sur le Diabète (France); Richard and Susan Family Foundation/American Diabetes Association Pinnacle Program Project; Roche; the Royal Society (UK); Russian Foundation for Basic Research (047.017.043); Sanofi-Aventis; Sarnoff Cardiovascular Research; Scottish Government Chief Scientist Office; SenterNovem (IOP Genomics grant IGE05012); Sigrid Juselius Foundation; the Skaraborg Institute, Skövde, Sweden; South Tyrolean Sparkasse Foundation; the Swedish Natural Sciences Research Council; The Swedish Research Council (349 2006-237P); the Association Diabète Risque Vasculaire (France); Topcon; the Wallenberg Foundation; and the Wellcome Trust (072960; 076113; 083270; 088885; 079557; 081682; 086596; 077016; 075491). A more complete list of acknowledgments is provided in the Supplementary Note.
Supplementary Note, Supplementary Figures 1 and 2 and Supplementary Tables 1–6
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Nature Reviews Endocrinology (2019)